Adenosine has been recognized as an important endogenous regulator of many physiological processes. It has variously been labeled a hormone, a neurotransmitter, a chemical mediator and an intracellular messenger. Its physiological effects are modulated by functional adenosine receptors which are widely distributed in mammalian tissues. There are at least two general classes of adenosine receptors which are involved in the regulation of physiological functions by adenosine including A.sub.1 -adenosine receptors, which are high affinity receptors which upon activation inhibit adenylate cyclase, and A.sub.2 -adenosine receptors, which are low affinity receptors which upon activation stimulate adenylate cyclase.
Adenosine has been implicated as a mediator of a wide variety of physiological processes including vasodilitation, cardiac depression, inhibition of lipolysis, vasoconstriction in the kidney, inhibition of platelet aggregation, inhibition of insulin release and potentiation of glucagon release in the pancreas, inhibition of lymphocyte functions, potentiation of histamine release from mast cells, and inhibition of neurotransmitter release from nerve endings. The A.sub.1 -adenosine receptor is involved in the antilipolytic, cardiac depressant and CNS depressant effects of adenosine. The A.sub.2 -adenosine receptor is involved in the hypotensive, vasodilatory, antithrombotic and endocrine effects of adenosine.
The wide variety of physiologic effects mediated by the adenosine receptors underscores the great potential utility for selective adenosine receptor agonists and antagonists as therapeutic agents in a variety of disease states. Various adenosine receptor agonists and antagonists have been identified and characterized. For example, the 1,3-dialkylxanthines, such as theophylline, have been shown to possess important therapeutic effects which are linked to their adenosine receptor antagonist activity.
Selective adenosine receptor agonists and antagonists will provide a specific physiological effect which would prove beneficial in a wide variety of disease states. For example, a selective A.sub.1 -adenosine receptor agonist would inhibit adenylate cyclase and provide a beneficial therapeutic effect by controlling tachycardia or by providing an analgesic, anticonvulsant or antidepressant effect. A selective A.sub.1 -adenosine receptor antagonist would relieve the inhibition of adenylate cyclase and provide a beneficial therapeutic effect as a cardiotonic agent, a bronchodilator or a cognition enhancing agent. A selective A.sub.2 -adenosine receptor agonist would stimulate adenylate cyclase and provide a beneficial therapeutic effect as a sedative.
It has now been found that the compounds of the present invention provide a selective A.sub.1 -adenosine receptor antagonistic effect. These compounds are useful in providing a cardiotonic effect in the treatment of patients suffering from congestive heart failure. These compounds are also useful in providing a cognition enhancing effect in patients suffering from Alzheimer's Disease. Furthermore, these compounds are useful in providing a bronchodilating effect in patients suffering from pulmonary bronchoconstriction.